Project Summary/Abstract This proposal describes a five year mentored laboratory training experience designed to lead to an independent academic career studying the genetics of neurodegenerative diseases. The candidate has both an M.D. and a Ph.D. as well as board certifications from the American Board of Pediatrics and the American Board of Medical Genetics and Genomics. The applicant?s career goal is to become a leading successful physician-scientist performing independently-funded research, continuing to make significant contributions to the field of neurodegenerative disease genetics. The career development plan includes training designed to broaden the applicant?s scientific skillset, including (1) computational tools and statistical analysis of large genetic datasets, (2) neurologic phenotypic characterization/data interpretation and (3) cellular approaches for functional validation of variants. This plan also incorporates additional training in leadership, mentorship, grant- writing skills, and ethics. There is a period of mentored research training which will include skills acquisition, didactic training, seminars, national meetings, an advisory committee and meetings with the mentor, followed by a transition to independence. The proposed research seeks to improve our understanding of the genetic underpinnings and pathophysiology of Parkinson?s disease (PD) by investigating a promising functional pathway related to lysosomal biology. There are over 50 lysosomal storage disorders (LSDs), which are diseases that result lysosomal dysfunction. Variants in GBA, the gene that causes the LSD Gaucher disease, increase the risk of PD. The associations of other LSD genes with PD are less clear. The overall goal of this project is to determine whether additional LSD genes increase risk of PD with the goals of improving PD diagnostics, risk prediction, and aiding in the development of novel therapies. The applicant proposes (1) studying families of individuals with LSDs to determine frequency of PD symptoms in carriers, (2) analyzing large genetic datasets of PD cases and controls to evaluate for associations between LSD genes and PD, and (3) testing LSD genetic variants using a cellular model for functional validation. This five year project will take place primarily at Baylor College of Medicine (BCM), an institution with nationally-recognized departments in both genetics and movement disorders, including well-established research efforts. The Department of Molecular and Human Genetics at BCM has a long track record of training early stage investigators to become highly successful translational researchers. The research environment provides the best intellectual environment and the best technology available. This proposal provides a broad research experience in family- based phenotypic characterization, analysis of large genomic datasets, and functional validation of variants of uncertain significance, and the proposed career development plan will prepare this applicant to become an independent physician-scientist and leader in the field of neurodegenerative disease genetics.